P06.06 A mutation-specific vaccine for Histone-3 K27M-mutated gliomas

• Published in: Neuro-oncology (Charlottesville, Va.) Vol. 19; no. suppl_3; p. iii50
• Main Authors: Ochs, K., Ott, M., Bunse, T., Sahm, F., Bunse, L., Keil, M., Deumelandt, K., Sonner, J., von Deimling, A., Wick, W., Platten, M.
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01.05.2017
• Subjects: POSTER PRESENTATIONS
• DOI: 10.1093/neuonc/nox036.180
• ISSN: 1522-8517

Contrary to the assumption that brain tumors are hardly immunogenic, immunotherapeutic approaches such as antigen-specific vaccines have become increasingly relevant in clinical trials for malignant gliomas. For instance, a point mutation in the gene for isocitrate dehydrogenase type 1 frequently present in adult diffuse gliomas has been shown to result in an immunogenic epitope currently targeted by an experimental vaccine in clinical trials. Another example of a recently discovered oncogenic mutation occurring especially in pediatric high grade midline gliomas is a point mutation in the histone-3 gene (H3F3A). Here, an amino acid exchange from lysine to methionine at position 27 (K27M) leads to reduction of H3.3 K27 trimethylation resulting in a distinct global methylation and gene expression pattern. Here, we analyzed the immunogenicity of H3.3 K27M and its relevance for a mutation-specific vaccination approach. Vaccination of major histocompatibility complex (MHC)-humanized (A2.DR1) mice with a H3.3 K27M-covering 27mer peptide induced CD8-driven mutation-specific immune responses. Using a human leukocyte antigen (HLA) epitope prediction algorithm, a mutation-containing 10mer peptide sequence with a strong binding affinity to HLA-A*02 was identified and subsequently confirmed as immunogenic class I neoepitope in vivo . Consequently, K27M peptide vaccination of A2.DR1 mice effectively inhibited growth of pre-established H3.3 K27M-expressing syngeneic tumors. Of clinical importance, mutation-specific cytotoxic T cells could be detected in the peripheral blood of patients with H3.3 K27M-mutated gliomas supporting the significance of K27M as immunogenic glioma neoepitope. Thus, our data provide evidence for a further clinical development of a vaccine targeting K27M for patients with H3.3 K27M-mutated gliomas.